The field of the invention is tumor suppression.
The mechanisms of tumorigenesis in vivo are poorly understood. Overwhelming evidence indicates that specific mutated forms of the p21.sup.ras gene (ras) contribute to tumorigenesis (Barbacid, M., 1987, Ann. Rev. Biochem., 56:779-827). When analyzed in a variety of neoplasms, the ras genes frequently contain characteristic point mutations that result in constitutive activation of p21.sup.ras (Barbacid, M., 1987, Ann. Rev. Biochem. 56:779-827; Bourne, H. R. et al., 1990, Nature 348:125-132). Expression of abnormally high levels of normal p21.sup.ras as a result of gene amplification or regulatory sequence mutations may also contribute to the transformation of normal cells to cancerous cells.
The ras genes which encode 21 kDa proteins are expressed ubiquitously and are found associated with the plasma membrane in the cytoplasm of the cell (Barbacid, M., 1987, Ann. Rev. Biochem. 56:779-827). p21.sup.ras is a guanine nucleotide-binding protein which catalyzes the hydrolysis of bound guanine triphosphate (GTP) to guanine diphosphate (GDP) (Barbacid, M., 1987, Ann. Rev. Biochem. 56:779-827; Bourne, H. R. et al., 1990, Nature, 348:125-132; Bourne, H. R. et al., 1991, Nature, 349:117-127) and is believed to be a key component of a complex intracellular signal transduction pathway from the plasma membrane to the nucleus. It is active when bound to GTP and inactive in its GDP-bound state.
Other proteins may be associated with p21.sup.ras. Such accessory proteins, such as mammalian GTPase activating protein (GAP or p120-GAP) and neurofibromin (NF1-GAP), the product of the neurofibromatosis type 1 gene locus (Trahey, M. et al., 1987, Science, 238:542-545; Trahey, M. et al., 1988, Science, 242:1697-1700; Vogel, U.S. et al., 1988, Nature, 335:90-93; Martin, G. A. et al., 1990, Cell, 63:843-849; Ballester, R. et al., 1990, Cell, 63:851-859), stimulate guanine nucleotide exchange as well as the intrinsic GTPase activity of p21ras (Bourne, H. R. et al., 1990, Nature 348:125-132). These proteins are collectively referred to as ras-GAPs.
In neurofibromatosis (NF type 1), an autosomal dominant disease characterized by various clinical disorders, including benign neurofibromas, constitutively-active p21.sup.ras has been attributed to nonfunctional neurofibromin (Basu, T. N. et al., 1992, Nature, 356:713-715; Li, Y. et al., 1992, Cell 69:275-281). Certain tumors unrelated to neurofibromatosis have also been found to contain mutated neurofibromin lacking GAP activity (Yatani, A. et al., 1990, Cell, 61:769-776).
The ras gene is the most frequently identified oncogene in human cancer, but oncogenic p21.sup.ras is resistant to the action of known mammalian ras-GAPs (Trahey, M. et al., 1987, Science, 238:542-545; Vogel, U.S. et al., 1988, Nature, 335:90-93).